Focal phospholipases A2 group III injections induce cervical white matter injury and functional deficits with delayed recovery concomitant with Schwann cell remyelination.

ABSTRACT

Phospholipases A(2) (PLA(2)) are group of enzymes that hydrolyze membrane phospholipids at the sn-2 position. PLA(2) are present in the brain and spinal cord and are implicated in several neurological disorders. Previously, we showed that PLA(2) activity increases following traumatic spinal cord injury and injection of group III secretory PLA(2) (sPLA(2)-III) demyelinates spinal cord axons. Here, we demonstrate that injections of sPLA(2)-III into the cervical dorsolateral funiculus (DLF) resulted in dose-dependent demyelination, loss of oligodendrocytes and astrocytes, as well as axonopathy. Additionally, spared axons within the lesion were remyelinated by Schwann cells between weeks 2 and 3. To assess functional loss and recovery, we employed a modified "Staircase Test" pellet retrieval device and footprint analysis of forelimb function during locomotion. Pellet retrieval assessment sensitively detected the dose dependent lesion and its recovery after sPLA(2)-III injections with greater sensitivity than footprint analysis. We believe that this is the first report of a reaching task being able to discriminate between various grades of cervical white matter damage and varying extents of recovery. Thus, our results indicate that sPLA(2)-III can create white matter pathologies that are remyelinated by Schwann cells 2 to 3 weeks after injury. Additionally, the pellet retrieval test is a sensitive and quantifiable method for assessing the dysfunction and later recovery mediated by sPLA(2)-III injections.